Anthracycline agents are antineoplastic and used in chemotherapy for the treatment of a broad spectrum of hematogenous and solid human malignancies, including breast cancer and leukemia. However, the utility of anthracyclines such as doxorubicin (Adriamycin®) is limited by cumulative and dose-related myocardial damage that may lead to congestive heart failure (CHF).1,2 It has been estimated that up to 20% of the patients treated with doxorubicin may develop CHF.3 
In addition to cumulative dose, age, combination therapy, hypertension, liver disease, chest-wall radiation from previous cancer treatment and preexisting cardiac disease are added risk factors for doxorubicin-induced CHF.4 
Despite its known cardiotoxicity, doxorubicin is one of the most widely used chemotherapy agents due to its effectiveness to prolong the life of cancer patients. It has been estimated that more than 50% of long-term survivors of childhood cancer were treated with doxorubicin or another anthracycline.5 However, many of the survivors who were treated with doxorubicin have long-term problems, often manifested as cardiac diseases. They often present as EKG changes and arrhythmias, or as a cardiomyopathy leading to CHF, as well as an increased risk of sudden death and death from cardiac causes.6 
Doxorubicin-induced cardiotoxicity is related to a patient's cumulative lifetime dose of doxorubicin. CHF is characterized by the reduced ability of the heart to pump blood, resulting in fluid retention and detrimental neuro-hormonal activation. Left untreated, CHF patients have a very high mortality rate. The underlying mechanism of this doxorubicin-induced cardiotoxicity is not clear. The only effective strategy of reducing the doxorubicin cardiotoxicity is to limit the exposure of doxorubicin. But this also limits the effectiveness of doxorubicin for treating the cancer.
Dexrazoxane (Zinecard®) is currently the only approved drug treatment for reducing anthracycline-induced cardiotoxicity with very limited benefits.6-8 Thus, there is an urgent and unmet medical need to develop treatments that are able to reduce doxorubicin-induced cardiotoxicity. Reducing the toxicity will also allow higher doses of doxorubicin to be safely administered to cancer patients.
Vasopressin (also known as antidiuretic hormone (ADH)) is a small nine-amino-acid peptide synthesized in the hypothalamus supraoptic and paraventricular nuclei and stored in the posterior pituitary. Its release is regulated by plasma osmolarity and blood volume/pressure.9 Vasopressin causes vasoconstriction via V1 receptors in vascular smooth muscle cells and water retention via V2 receptors in the kidney collecting ducts.10 
Vasopressin levels are frequently elevated in cancer patients.11-14 Hyponatremia, due to abnormally high levels of vasopressin, is also very common in patients with cancer.12, 15 Furthermore, high serum vasopressin levels have been shown to be correlated to the low survival rate of small-cell lung cancer patients,16 indicating a detrimental role of vasopressin in cancer patients.
Studies have shown that doxorubicin may increase the level of vasopressin. In doxorubicin-treated rats, the expression of vasopressin and aquaporin-2 water channel, which transport water from a collecting duct in the kidney to the blood circulation, is elevated.17 Furthermore, doxorubicin-treated rabbits have an increased sensitivity to vasopressin.18 
Accumulating evidence suggests that vasopressin may play an important role in the development and progression of CHF: vasopressin and aquaporin-2 water channel levels are increased in CHF19-22 and V2 antagonists have shown benefits in lessening congestion and improving symptoms in subjects with CHF.23, 24 Water retention and systemic edema are the hallmarks of CHF.
Previously, a few studies investigated the potential of vasopressin antagonists to reduce doxorubicin-induced cardiac injury and to promote survival in experimental animals. It was found that vasopressin antagonists may alleviate the symptoms of CHF18 caused by doxorubicin injection. However, in a previous study, OPC-31260, a vasopressin V2 receptor antagonist, had a slight but not significant reduction of mortality rate in doxorubicin-treated rats.25 Thus, although these studies demonstrated benefits of vasopressin antagonists in treating doxorubicin-induced toxicity, the effects were not remarkable. In these previous studies, vasopressin antagonists were given several weeks after the administration of doxorubicin. Thus, permanent myocardial injury may have already occurred before the initiation of vasopressin antagonist therapy. Importantly, models in these previous studies may not faithfully reproduce an elevated vasopressin environment as often found in cancer patients since only normal healthy rats were used. An experimental model with elevated vasopressin may be ideal for the evaluation of the therapeutic potential of V2 antagonists.